Millions of Americans suffer from unrelieved persistent pain, which has a devastating effect on their quality of life and severely burdens our health care system. There is growing evidence that intractable pain is frequently comorbid with anxiety, depression, and other psychological traits, often manifesting as hypersensitivity disorders in which the underlying physical substrate of the pain is unknown. The role of cognitive and affective risk factors in the development of these idiopathic pain conditions has not been adequately explored. A compelling explanation for the development of idiopathic disorders, such as fibromyalgia, irritable bowel syndrome, and temporomandibular joint disease (TMD), is disregulation of the adrenergic neurotransmitter system. Polymorphic variants of several genes encoding adrenergic receptors have been shown to elevate risk for developing TMD;these genes have also been associated with negative mood and cognitive effects. This proposal will investigate the relationship between alpha-adrenergic receptor (ADRA) gene polymorphisms and risk factors for chronic pain using genetic techniques and murine models of behavior. Our preliminary studies with a small prospective cohort showed a strong link between genetic variants of ADRA1A and risk of TMD development. Here we would like to employ a novel case control study population to verify and extend these preliminary findings. To confirm the contribution of alpha-adrenergic receptors to pain sensitivity and affective states in vivo, we will use mouse inflammatory pain and behavioral models. To investigate potential molecular mechanisms underlying the observed associations, individual variations in ADRA1A expression patterns will be studied in white blood cell samples collected from each subject enrolled in the study. These experiments will provide a better understanding of how adrenergic neuromodulation contributes to pathological nociceptive and affective states, ultimately leading to the development of a persistent pain condition. Identifying genetic and environmental risk factors for TMD will allow for the development of precise diagnostic tools, and provide novel targets for analgesic therapies. Determining the genetic and environmental risk factors for the development of persistent pain disorders such as TMD is crucial for diagnosing and treating these debilitating diseases. This proposal will explore the causes of TMD in a population of chronic pain patients, and investigate the molecular mechanisms by which adrenergic receptors contribute to pain sensitivity and negative mood traits.